Longitudinal microbiome-host interactions and clinical outcomes in drug-resistant tuberculosis patients

耐药结核病患者的纵向微生物组-宿主相互作用和临床结果

• 批准号: 10672997
• 负责人: Charissa Camille Naidoo
• 金额: $ 8.93万
• 依托单位: STELLENBOSCH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-27 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672997
• 关键词: 16S ribosomal RNA sequencing; Acetates; Adolescent; Adult; Affect; African; Aftercare; Anaerobic Bacteria; Antibiotic Therapy; Antibiotics; Antitubercular Antibiotics; Butyrates; Cause of Death; Clinical; Clinical Trials; Collaborations; Combined Antibiotics; Computing Methodologies; Data; Dedications; Dietary Supplementation; Dose; Drug Kinetics; Drug resistance in tuberculosis; Enterobacter; Enterobacteriaceae; Epidemic; Ethambutol; Etiology; Feces; Foundations; Funding; Future; HIV; Health; Health Benefit; Hospitals; Human Microbiome; Immune; Inflammatory; Injections; Intervention; Klebsiella; Knowledge; Leukocytes; Levaquin; Life; Linezolid; Mass Chromatography; Mass Fragmentography; Mass Spectrum Analysis; Measures; Mediator; Mentors; Mentorship; Metabolic; Metadata; Monitor; Multidrug-Resistant Tuberculosis; Mus; New York; Oral; Outcome; Pantoea; Parents; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Physiological; Production; Propionates; Prospective, cohort study; Province; Pulmonary Tuberculosis; Pyrazinamide; Regimen; Research; Research Priority; Research Support; Resistance; Rifampicin resistance; Rifampin; Sampling; Scientist; South Africa; South African; Sputum; Structure; Testing; Treatment outcome; Tuberculosis; Uncertainty; Universities; Volatile Fatty Acids; Withholding Treatment; Work; absorption; career; career development; cohort; combinatorial; commensal microbes; design; diagnostic tool; drug-sensitive; experimental study; global health emergency; gut microbiota; host microbiome; human microbiota; immunoregulation; improved; isoniazid; longitudinal analysis; low and middle-income countries; medical schools; microbial; microbial community; microbial host; microbiome; microbiome research; microbiota; microbiota profiles; mortality; multidisciplinary; programs; resilience; response; risk prediction; treatment response; tuberculosis drugs; tuberculosis treatment

PROJECT SUMMARY The human microbiome is an essential mediator of health and influences important metabolic functions through production of short chain fatty acids (SCFAs). These compounds have been shown to independently predict risk for developing tuberculosis (TB) – a leading cause of death in South Africa. Antibiotics may profoundly impact the microbiome yet the impact of treatment on the microbiome remains completely uncharacterized in patients with rifampicin-resistant and multidrug-resistant tuberculosis (RR/MDR-TB; resistance to the two most effective TB drugs). In response to the RR/MDR-TB epidemic, the South African National Programme rolled-out an all- oral shorter course regimen (SCR) which is being investigated within the funded observational prospective cohort study (SHIFT-TB; PI: Dr Graeme Meintjes) that this proposal (NASCENT; PI: Dr Charissa Naidoo) will leverage. We hypothesize that the SCR, though comprising lifesaving antibiotics for TB, also contain others which could plausibly affect the commensal microbiota (≤540 broad-spectrum antibiotic doses given over 9 months). Using 16S rRNA gene sequencing, we will longitudinally characterize the sputum and stool microbiota in 260 RR/MDR- TB adults and adolescents (≥ 15 years) initiating the SCR at Nkqubela Hospital, Eastern Cape Province, South Africa, at five intervals before, during, and after treatment. We will correlate the microbiota with important clinical metadata measured in the parent study, including repeated pharmacokinetic (Pk) data and pre-defined clinical outcomes. This work will lay the foundation for future trials where the microbiome is monitored as a diagnostic tool for clinical outcomes or modulated (through dietary supplementation, host-directed therapies) to improve long-term health (i.e., post-TB lung sequalae). Specifically, Aim 1 will evaluate changes in the sputum and stool microbiota in patients receiving treatment for RR/MDR-TB. Aim 2 will, using targeted as chromatography-mass spectrometry in stool, longitudinally quantify microbially-produced SCFAs (butyrate, propionate, acetate) and correlate SCFAs with the microbiota in co- occurrence network analyses. Aim 3 will evaluate longitudinal associations between the microbiota and drug Pk (where we expect greater drug absorption to result in greater microbial shifts and loss of diversity), and whether distinct microbiomes reflect favorable vs. unfavorable outcomes. Together, the proposal will achieve the following: 1) promote an independently funded research career for the candidate at Stellenbosch University (through structured mentorship with scientific experts), 2) strengthen South African analytical capacity for microbiome research in a low-middle income country (LMIC) research priority (TB), 3) and enhance long term collaboration with leading US scientists.

项目概要 人类微生物组是健康的重要介质，通过以下方式影响重要的代谢功能： 这些化合物已被证明可以独立预测风险。 结核病（TB）是南非的一个主要原因，抗生素可能会产生深远的影响。 微生物组，但治疗对患者微生物组的影响仍然完全未知 耐利福平和耐多药结核病（RR/MDR-TB；对两种最有效的耐药结核病） 结核病药物）。为了应对 RR/MDR-TB 流行病，南非国家计划推出了一项全面的计划。 口服短程治疗方案（SCR）正在资助的观察性前瞻性队列中进行研究 该提案（NASCENT；PI：Charissa Naidoo 博士）将利用该研究（SHIFT-TB；PI：Graeme Meintjes 博士）。 我们认为，SCR 虽然包含治疗结核病的救命抗生素，但也包含其他可能 可能会影响共生微生物群（9 个月内给予≤540 剂广谱抗生素）。 16S rRNA 基因测序，我们将纵向表征 260 RR/MDR- 中的痰和粪便微生物群 南开普省 Nkqubela 医院的结核病成人和青少年（≥ 15 岁）开始 SCR 非洲，在治疗前、治疗期间和治疗后的五个时间间隔，我们将微生物群与重要的临床相关联。 母研究中测量的元数据，包括重复的药代动力学 (Pk) 数据和预定义的临床数据 这项工作将为未来监测微生物组作为诊断的试验奠定基础。 临床结果或调节（通过膳食补充剂、宿主定向疗法）以改善的工具 长期健康（即结核病后肺后遗症）。 具体来说，目标 1 将评估接受以下治疗的患者痰液和粪便微生物群的变化： 目标 2 将使用粪便中的靶向色谱-质谱法进行纵向定量。 微生物产生的 SCFA（丁酸盐、丙酸盐、乙酸盐）并将 SCFA 与微生物群相关联 目标 3 将评估微生物群和药物 Pk 之间的纵向关联。 （我们预计更大的药物吸收会导致更大的微生物变化和多样性丧失），以及是否 不同的微生物组反映了有利与不利的结果。 该提案将共同实现以下目标：1）促进独立资助的研究事业 斯泰伦博斯大学的候选人（通过科学专家的结构化指导），2）加强南方 非洲中低收入国家 (LMIC) 研究重点 (TB) 微生物组研究的分析能力， 3）并加强与美国领先科学家的长期合作。